Alzheimer’s Holy Grail

Finding those answers lured Wilcock and Dage to IU School of Medicine. Their arrival added even more depth to an abundant bench of talented researchers in neurodegenerative disorders. Advances in diagnosing and treating Alzheimer’s have taken time, but that progress is rapid compared to work in vascular dementia, Lewy body disease, and Parkinson’s disease.

“That’s what I was brought here for,” said Wilcock, who earlier this year uprooted her lab from the University of Kentucky’s Sanders-Brown Center on Aging. “I want us finding and validating biomarkers for all the other dementia-causing pathologies.”

For Dage, the journey to IU was much shorter, barely a mile from Lilly’s corporate and research hub. Despite the proximity, Dage admitted he “didn’t really have a full appreciation for the nature of the work that’s going on” at IU.

Clarity came when he needed samples for a project related to rare neurodegenerative disorders known as frontotemporal dementia. Dage reached out to an NIH-backed repository at IU, the nation’s largest biobank for dementia. During Dage’s conversations with Tatiana Foroud, PhD, who oversees the facility, talk turned to the possibility of Dage helping set up a biomarker lab.

Lilly agreed to cover 10 percent of his time to work on the project, but Dage quickly realized it was far too small. To pursue the project and innovative work would mean leaving the pharmaceutical giant, which he did in 2021. Moving to the School of Medicine "was an opportunity to blaze a new path for myself," he said.

THE BLOOD TEST Dage helped design might serve as a template for discovering biomarkers for other diseases. But in 2014, his idea to look in blood for a biomarker of a disease occurring in the brain was met with skepticism. Then, Dage's team at Lilly needed biomarkers to test the potential of drugs to act on a target. That search led them to an intriguing protein: phosphorylated tau.

Set aside all the syllables and think of tau this way: cargo transport. Neurons in our brain have cell bodies, a long axon, and synapses at the end. Those synapses—and the signals they fire off—regulate our memory, motor skills, and behavior. To keep that network online, neurons ship proteins from one end to the other. T

au acts to facilitate the shipping service, passing those packages along. It also needs a place to anchor for stability, which is done at phosphorylation sites, giving us the moniker “p-tau.” But those proteins can get stuck and misfolded, creating snags that grow into the trademark tangles in Alzheimer's.

Eventually, those tangles block the shipping lane, stressing neurons to the point they die. When that happens, tangles are chopped up and excreted. Faint traces filter into the bloodstream.

So, what makes Dage’s version unique? The antibodies it uses don't occur naturally: They were designed for this specific purpose. "We really spent a lot of time engineering those tools to make the test what it is," Dage said. To test its performance, the drug company partnered with several academic institutions around the world, led by the Mayo Clinic in Rochester, Minnesota, Lund University in Sweden and University of California, San Francisco.

It's hard to understate the potential importance of this discovery. Instead of ordering expensive scans or subjecting patients to spinal taps, a physician would need only perform a blood draw and send the vial for a low-cost analysis. Expanding the pool of people screened will matter everywhere, but Dage notes it will be incredibly impactful in less advantaged countries globally or rural areas in the U.S., where specialists are not available and primary care is essential to meeting patient needs.

"It's going to give people who have no access to advanced techniques the possibility of one day getting tested at their local clinic or CVS," he said.

Developing drugs and biomarkers in tandem is also likely to be a staple in the future. "That's why it felt so quick with Alzheimer's," Wilcock noted. "Everything just converged at the same point."

EXPANDING THE GRID to find new markers is where Wilcock comes in.

Set aside drug development for a moment. Without those markers, researchers still struggle to precisely articulate how some neurodegenerative disorders unfold and what mechanisms power them. Even when they have candidates, verifying the scope of their role is vexing.

At Kentucky, Wilcock's lab relied on an autopsy cohort—individuals who agreed to donate their brains, tissue samples, and medical histories—to vet candidates. Sometimes, translational research isn't linear.

A prime example is discovering a potential marker for vascular dementia, where regions of the brain are deprived of oxygen and critical nutrients. To cope, the brain tries to grow new vessels to boost its supply, a process that uses specific proteins. So, Wilcock’s lab used stored samples of patients’ spinal fluid to see which of these growth factors the brain relies on. The results showed a potentially odd culprit: placental growth factor. Usually, that protein is found in the umbilical cord, where large blood vessels support a developing child. It’s also present in other tissues but at very low levels. “What in the world is that protein doing in the brain?" Wilcock said.

"Not only was there more of that protein around, but higher amounts were associated with white matter changes in a patient’s brain. "Nobody had ever considered it in the context of brain disease."

Those findings served as the basis for a grant from the National Institutes of Health, a portion of which Wilcock transferred to IU. The experience reinforces an integral lesson. "People assume translation goes from a test tube to animal models to a human," she said. "But there's also the ability to work backward."

Wilcock knows it's not enough to find a thread to pull on from individuals who have already died from their condition. "We don't know which symptom was the first to appear and when clinical symptoms began to appear," she said. "Which one tipped them over the edge to start having severe cognitive problems?"

Dage and Wilcock are still settling into their respective roles at IU, but they fill a long-sought niche. Aside from its biorepository, IU is home to three NIH-supported centers focused on Alzheimer’s. One, led by Bruce Lamb, PhD, develops new mouse models. Lamb partnered with Alan Palkowitz, PhD, to oversee the TREAT-AD center, which vets previously unexplored drug targets. The third is the Indiana Alzheimer’s Disease Research Center, led by Andrew Saykin, PsyD, which focuses on studying the disease in human participants. Liana Apostolova, MD, also spearheads work in early-onset Alzheimer's.

What's impressed Dage is the degree to which those disciplines blend through the Stark Neuroscience Research Institute. "IU is in a class of its own with their camaraderie and collaboration." It will also come in handy as Dage expands his scope into other neurodegenerative disorders.

Wooing Dage is also an obvious coup, Wilcock said. "Jeff is a critical piece, and if we could clone him twice, that would be awesome," she added.

Next comes recruiting other talented researchers—and her pitch line is straightforward. "We want this to become a destination for precision health in dementia," she said.

Your support helps world-class researchers speed up the search for ways to detect neurodegenerative diseases. To learn how you can help, contact Andrea Spahn-McGraw at 317-278-2124 or anspahn@iu.edu.